WO2007010111A1

WO2007010111A1 - Method for preparing mono- or difluorinated hydrocarbon compounds

Info

Publication number: WO2007010111A1
Application number: PCT/FR2006/001648
Authority: WO
Inventors: Laurent Saint-Jalmes; Daniel Uguen
Original assignee: Rhodia Chimie; Cnrs
Priority date: 2005-07-19
Filing date: 2006-07-07
Publication date: 2007-01-25
Also published as: FR2888845A1; US20090234151A1; CN101203472A; JP2009501770A; FR2888845B1; EP1904425A1

Abstract

The invention concerns a method for preparing mono- or difluorinated hydrocarbon compounds. The inventive method for preparing mono- or difluorinated hydrocarbon compounds from an alcohol or a carbonylated compound includes reacting one of them with a fluorinating reagent, optionally in the presence of a base. The invention is characterized in that the fluorinating agent is a reagent comprising a pyridinium motif corresponding to formula (F), wherein R0 represents an alkyl or cycloalkyl group.

Description

PROCESS FOR THE PREPARATION OF HYDROCARBON COMPOUNDS

MONO- OR DIFLUORES.

The present invention relates to a process for the preparation of mono- or difluorinated hydrocarbon compounds.

Fluorinated compounds are generally difficult to access. The reactivity of the fluorine is such that it is difficult or impossible to directly obtain the fluorinated derivatives.

One of the most widely used techniques for producing the fluorinated derivative is to react a halogenated derivative, generally chlorinated, to exchange the halogen with a mineral fluorine, generally an alkali metal fluoride, most often of high atomic weight. In general, the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise.

Under these conditions, many processes such as those described in FR 2 353 516 and in the article Chem. Ind. (1978) - 56 have been described and implemented industrially to obtain aryl fluorides aryl on which are grafted electron-withdrawing groups.

Except in cases where the substrate is particularly suitable for this type of synthesis, this technique has drawbacks, the main ones are those which will be analyzed below.

The reaction requires reagents such as alkali metal fluorides such as potassium fluoride which are made relatively expensive by the specifications they must meet to be suitable for this type of synthesis; they must be very pure, dry and in a suitable physical form.

Reagents such as liquid hydrofluoric acid or diluted by aprotic dipolar solvents are also used. However, hydrofluoric acid is a too powerful reagent and often leads to unwanted polymerization reactions or tars.

In this case, and especially in the case where it is desired fluorinated derivatives on a carbon type alkyl (including aralkyl) depleted electron by the presence of electro-attractor type groups, the skilled person is in front of an alternative whose terms are hardly encouraging; either very hard conditions are chosen and tar is obtained mainly, or it is placed under mild reaction conditions and the unchanged substrate is found in the best case. Finally, it should be noted that some authors have proposed exchanges using as reagent salts of hydrofluoric acid in the presence of heavy elements in the form of oxides or fluorides. Among the elements used are antimony and heavy metals such as silver or mercury. It is important to find mild fluorination conditions, in particular for converting carbon-oxygen bonds to carbon-fluorine bonds.

It has already been proposed fluorination reagents for performing this type of reaction. It is known to use an aminosulfur trifluoride (especially diethylaminosulfur trifluoride (DAST)) as a fluorinating agent (J. Org Chem., 40, 3808 (1975); Tetrahedron, 44, 2875 (1988); Fluorine Chem., 43 (3), 405-13, (1989) and 42 (1), 137-43, (1989), EP 0 905 109). In particular, it makes it possible to convert a carbonyl group into a difluoromethylene group. The disadvantage of DAST is to lead to malodorous byproducts, difficult to eliminate from the reaction medium.

H. Hayashi et al have described 2,2-difluoro-1,3-dimethylimidazoline as a novel fluorinating agent for the conversion of alcohols to monofluorinated compounds and aldehydes / ketones to gem-difluorinated compounds. Said reagent does not seem very stable and the announced yields are difficult to access.

It was therefore desirable to have an improved process for performing the fluorination under better conditions.

It has now been found and this is the object of the present invention, a process for the preparation of a mono- or difluorinated hydrocarbon compound from an alcohol or a carbonyl compound which comprises the reaction one of them with a fluorination reagent, optionally in the presence of a base, which is characterized in that the fluorinating agent is a reagent comprising a pyridinium unit corresponding to the following formula:

in said formula:

- Ro represents an alkyl or cycloalkyl group. In the present text, the term "alkyl" is intended to mean a linear or branched hydrocarbon-based chain containing from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms.

Examples of preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl.

By "cycloalkyl" is meant a cyclic, monocyclic hydrocarbon group comprising from 3 to 7 carbon atoms, preferably from 5 to 6 carbon atoms.

It should be noted that the group Ro could have another meaning, for example, benzyl but from an economic point of view, there is no point in having a complicated group R ₀ . Thus, C ₁ -C ₄ alkyl groups are preferred and more particularly the methyl group.

According to the process of the invention, the fluorination is carried out using the fluorinating reagent of an alcohol or a carbonyl compound, aldehyde or ketone.

A first embodiment of the invention consists in preparing a monofluorinated compound from a corresponding hydroxyl compound (alcohol).

Another variant of the invention consists in preparing a gifluorinated compound from a carbonyl compound.

In the process of the invention, a fluorination reagent comprising the unit having the formula (F) is involved.

A preferred reagent is to use 1-alkyl- or 1-cycloalkyl-2-fluoropyridinium but the invention also contemplates the case where said unit is included in a polycyclic structure such as for example the pyridinium ring is attached to a ring having 5 or 6 carbon atoms, saturated, unsaturated or aromatic.

As more specific examples, there may be mentioned 1-alkyl- or 1-cycloalkyl-2-fluoroquinolinium. The invention does not exclude the presence of one or more (at most 4) substituents on one or more rings of the reagent, in particular on the pyridinium ring.

As examples given by way of illustration, mention may in particular be made of alkyl or alkoxy groups having from 1 to 4 carbon atoms, a halogen atom (F, Cl, Br, I) or an electron-withdrawing group, for example nitro, carboxylate. alkyl having 1 to 4 atoms.

According to another variant embodiment of the invention, the fluorinated reagent can be prepared in situ by using, associated with a source of fluoride, a halogen reagent comprising a pyridinium unit corresponding to the following formula:

in said formula: X represents a halogen atom of higher rank than fluorine, preferably chlorine, bromine or iodine,

- Ro represents an alkyl or cycloalkyl group.

It should be noted that in the pyridinium unit of formula (F) or (Fi), the nitrogen atom is quaternized. The counter-ion associated with it and symbolized by Y ^" results from the process for preparing said unit, and is preferably a halide, a sulphonate group or a carboxylate group.

As examples of halides, mention may be made of fluoride, chloride, bromide or iodide.

As for the sulphonate group, it can be represented by the formula R _a Sθ ₃ ^" in which R _a is a hydrocarbon group.

In said formula, R _a is a hydrocarbon group of any kind. However, it is interesting from an economic point of view that R _a is of a simple nature, and more particularly represents a linear or branched alkyl group having 1 to 4 carbon atoms, preferably a methyl or ethyl group but it may also represent for example a phenyl or tolyl group or a trifluoromethyl group. Among the groups R _a SO ₃ ^' , the preferred group is a triflate group which corresponds to a group R _a representing a trifluoromethyl group.

Y ^" may also be a carboxylate group which may be represented by the formula R _b CO ₂ ^" wherein R _b is a hydrocarbon group.

As for the sulfonate group, the nature of R _b is not critical, but it is economically desirable for R _{b to} be an alkyl group having 1 to 4 carbon atoms, preferably a methyl group.

As fluorination reagents used preferentially in the process of the invention, mention may be made in particular of:

2-fluoro-N-methylpyridinium tosylate,

2-fluoro-N-methylpyridinium triflate,

2-fluoro-N-methylpyridinium fluoride,

N-methyl-2-fluoroquinolium triflate, N-methyl-2-fluoroquinolinium fluoride. The amount of fluorination reagent used is expressed relative to the amount of substrate, alcohol or carbonyl compound. It is preferably at least equal to the stoichiometric amount. It is such that the ratio between the number of moles of fluorination reagent and the number of moles of substrate varies most often between 1 and 3 and is preferably between 1, 5 and 2.

According to the process of the invention, an alcohol or a carbonyl compound is reacted with the fluorination reagent of the invention, in the presence of a base and in an organic medium. Alcohol

With regard to alcohol, it responds more particularly to the general formula (I):

R ₁ - OH (I) in said formula (I): - Ri represents a hydrocarbon group having from 1 to 30 carbon atoms, which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic cycloaliphatic group; a saturated or unsaturated, linear or branched, aliphatic group carrying a cyclic substituent. The alcohol which is involved in the process of the invention corresponds to formula (I) in which R 1 represents a linear or branched, saturated or unsaturated acyclic aliphatic group.

More specifically, R 1 represents an alkyl, alkenyl, alkadienyl, alkynyl, linear or branched group preferably having from 1 to 30 carbon atoms. The hydrocarbon chain can be optionally:

- interrupted by one of the following groups:

-O-, -CO-, -COO-, -OCOO-, -S-, -SO ₂ -, -NR ₂ -, -CO-NR ₂ -, in these formulas R ₂ represents hydrogen or an alkyl group preferably a methyl or ethyl group, and / or carrier of one of the following substituents:

-OH, -OCOO-, -COOR ₂ , -CHO, -NO ₂ , -X, -CF ₃ , in these formulas, R ₂ having the meaning given above. The acyclic, saturated or unsaturated, linear or branched aliphatic residue may optionally carry a cyclic substituent. By ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.

The acyclic aliphatic residue may be linked to the ring by a valency bond or by one of the following groups:

-O-, -CO-, -COO-, -OCOO-, -S-, -SO ₂ -, -NR ₂ -, -CO-NR ₂ -, in these formulas, R ₂ having the meaning given above. As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring or benzenes. In the general formula (I) of the alcohols, R 1 can also represent a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 to 7 carbon atoms, preferably 6 carbon atoms in the ring.

Preferred examples of R 1 groups include cyclohexyl or cyclohexenyl.

It should be noted that since the group R 1 represents a ring, the invention also includes the case where the ring may carry one or more substituents insofar as they do not interfere with the process of the invention. Mention may in particular be made of alkyl or alkoxy groups having from 1 to 4 carbon atoms. The process is easily carried out with most alcohols.

More specific examples of alcohols include:

lower aliphatic alcohols having from 1 to 5 carbon atoms, such as, for example, methanol, ethanol, trifluoroethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, dry alcohol, butyl alcohol, tert-butyl alcohol, pentanol, isopentyl alcohol, dry-pentyl alcohol and tert-pentyl alcohol, ethylene glycol monoethyl ether, methyl lactate, isobutyl lactate, methyl D-lactate, isobutyl D-lactate,

higher aliphatic alcohols having at least 6 and up to about 20 carbon atoms, such as, for example, hexanol, heptanol, isoheptyl alcohol, octanol, isooctyl alcohol, ethyl- 2 hexanol, sec-octyl alcohol, tert-octyl alcohol, nonanol, isononyl alcohol, decanol, dodecanol, tetradecanol, octadecanol, hexadecanol, oleyl alcohol, alcohol eicosylic, diethylene glycol monoethyl ether.

cycloaliphatic alcohols having from 3 to about 20 carbon atoms, such as, for example, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, cyclooctanol, cyclododecanol, tripropylcyclohexanol, methylcyclohexanol and methylcycloheptanol, cyclopenten-ol, cyclohexen-ol,

an aliphatic alcohol bearing an aromatic group having from 7 to about 20 carbon atoms, such as, for example, benzyl alcohol, phenethyl alcohol, phenylpropyl alcohol, phenyloctadecyl alcohol and naphthyl decyl alcohol.

It is also possible to use polyols, in particular polyoxyethylene glycols such as, for example, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol and glycerol.

Among the abovementioned alcohols, the aliphatic or cycloaliphatic alcohols, preferably primary or secondary aliphatic alcohols having 1 to 4 carbon atoms, are preferably used in the process of the invention. A variant of the process of the invention consists in using a terpene alcohol and more particularly a terpene alcohol of formula (Ia):

T - OH (la) in said formula (la):

- T represents the remainder of a terpene alcohol having a number of carbon atoms multiple of 5.

In the following description of the present invention, the term "terpene" is intended to mean oligomers derived from isoprene.

More specifically, the alcohol used has the general formula (Ia) in which the residue T represents a hydrocarbon group having from 5 to 40 carbon atoms and more particularly a linear or branched, saturated or unsaturated aliphatic group; a cycloaliphatic, saturated, unsaturated or aromatic, monocyclic or polycyclic group, comprising rings having from 3 to 8 carbon atoms.

It will be specified, without limiting the scope of the invention, that the remainder T represents the rest:

an aliphatic terpene alcohol, saturated or unsaturated, linear or branched,

a cycloaliphatic, monocyclic, saturated or unsaturated terpene alcohol, or aromatic,

- A polycyclic cycloaliphatic terpene alcohol comprising at least two carbocycles, saturated and / or unsaturated.

Regarding the remainder T of a saturated or unsaturated, linear or branched aliphatic terpene alcohol, the number of carbon atoms varies between 5 and 40 carbon atoms. As more specific examples of residue T, there may be mentioned groups comprising 8 carbon atoms, saturated or having a double bond, and bearing two methyl groups, preferably in position 3 and 7.

When it is a monocyclic compound, the number of carbon atoms in the ring can vary widely from 3 to 8 carbon atoms, but is preferably 5 or 6 carbon atoms. The carbocycle may be saturated or comprising 1 or 2 unsaturations in the ring, preferably 1 to 2 double bonds which are most often in position α of the oxygen atom.

In the case of an aromatic terpene alcohol, the aromatic ring is usually a benzene ring.

The compound may also be polycyclic, preferably bicyclic which means that at least two rings have two carbon atoms in common.

In the case of polycyclic compounds, the number of carbon atoms in each ring varies between 3 and 6: the total number of carbon atoms is preferably equal to 7.

Examples of bicyclic structure, commonly encountered, are given below:

[4.1, 0] [2.2.1] [3.1, 1] [3.2.0] In the case of a ring, the presence of substituents is not excluded in that they are compatible with the intended application. The substituents most often carried by the carbocycle are one or more alkyl groups, preferably three methyl groups, a methylene group (corresponding to an exocyclic bond), an alkenyl group, preferably an isopropenyl group.

Examples of terpenic alcohols that may be used include:

saturated or unsaturated aliphatic terpene alcohols such as:

. 3,7-dimethyloctanol, the hydroxycitronellol,

. 1-hydroxy-3,7-dimethyl-7-octene,

. nerol,

. geraniol,

. the linalool,. citronellol,

aromatic cycloaliphatic terpene alcohols such as:

. thymol,

saturated or unsaturated monocyclic or polycyclic cycloaliphatic terpene alcohols such as: chrysanthemic alcohol,

. 1-hydroxyethyl 2,2,3-trimethylcyclopentane, . β-terpineol,

. 1-methyl-3-hydroxy-4-isopropylcyclohexene,

. the α-terpineol,

. terpinene-4-ol,. 1,3,5-trimethyl 4-hydroxymethylcyclohexene,

. isoborneol,

Of all the abovementioned alcohols, the preferred alcohols are as follows:

. chrysanthemic alcohol,

. 3,7-dimethyloctanol, geraniol,

. the linalool,

. citronellol,

. the hydoxycitronellol,

. nerol,. thymol,

. menthol,

. isoborneol,

Carbonyl compound May intervene in the process of the invention, as substrates, an aldehyde or a ketone (or dione) corresponding to one of the general formulas:

(II) or ^Rs (III) or ^Rs (IV) in said formulas:

R ₃ , R ₄ and R ₅ , which may be identical or different, represent a hydrocarbon group comprising from 1 to 40 carbon atoms, which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a sequence of the aforementioned groups,

the groups R ₄ and R ₅ may be bonded together to form a ring comprising 5 or 6 atoms,

the groups R ₄ and R ₅ do not comprise any hydrogen atoms on the carbon atom in position α with respect to the carbonyl group.

The invention can use symmetrical ketones or diones if in the formulas (III) or (IV), R ₄ is identical to R ₅ and asymmetric ketones or diones if R ₄ is different from R ₅ . More specifically, in the formulas (II) to (IV), R ₃ , R ₄ and R ₅ represent a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a saturated or unsaturated, linear or branched, aliphatic group carrying a cyclic substituent.

R ₃ , R ₄ and R ₅ preferably represent a linear or branched saturated acyclic aliphatic group preferably having from 1 to 12 carbon atoms, and even more preferably from 1 to 4 carbon atoms. The invention does not exclude the presence of unsaturation on the hydrocarbon chain such as one or more double bonds which may or may not be conjugated, or a triple bond.

The hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group to the extent that it does not react and there may be mentioned in particular a group such as in particular -CO-.

The hydrocarbon chain may optionally carry one or more substituents (for example, halogen, ester) insofar as they do not interfere with the ketone reaction. The acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent. By ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.

The acyclic aliphatic group may be linked to the ring by a valence bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulphonyl, etc.

As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 ring carbon atoms or benzenes, these cyclic substituents being themselves optionally carrying any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention. In particular, alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.

Among the aliphatic groups bearing a cyclic substituent, cycloalkylalkyl groups, for example cyclohexylalkyl or aralkyl groups having 7 to 12 carbon atoms, in particular benzyl or phenylethyl, are more particularly targeted.

In the formulas (III) or (IV), R ₃ , R ₄ and R ₅ may also represent a saturated or unsaturated carbocyclic group preferably having 5 or 6 carbon atoms. carbon in the cycle; a heterocyclic group, saturated or unsaturated, in particular containing 5 or 6 atoms in the ring, including 1 or 2 heteroatoms such as nitrogen, sulfur and oxygen atoms; an aromatic or monocyclic aromatic carbocyclic or heterocyclic group, preferably phenyl, pyridyl, pyrazolyl, imidazolyl or polycyclic fused or unsubstituted, preferably naphthyl.

Since one of the groups R ₃ , R ₄ and R ₅ comprises a ring, this ring may also be substituted. The nature of the substituent can be any as long as it does not interfere with the main reaction. The number of substituents is generally at most 4 per cycle but most often equal to 1 or 2.

Among all the meanings given above, R ₃ preferably represents a linear or branched alkyl group having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms or a phenyl group. As mentioned previously, the groups R ₄ and R ₅ do not comprise hydrogen atoms on the carbon atom in position α with respect to the carbonyl group.

Thus, the carbon atoms in position α with respect to the carbonyl group are tertiary carbon atoms. An example of a tertiary carbon atom may be represented by the formula (R ₆ ) (R 7) (Re) C - in which R ₆ , R ₇ and R ₈ represent, in particular, a halogen atom, preferably an atom fluorine; a linear or branched alkyl group having 1 to 6 carbon atoms; the groups R ₆ , R ₇ and R ₈ can also form a ring, for example a phenyl group optionally included in a polycyclic structure, for example of the naphthalenic type.

In formulas (III) and (IV), the groups R ₄ and R ₅ may be bonded together to form a ring comprising 5 or 6 atoms: the carbon atoms located in the α position on either side of the carbonyl group [ formula (III)] or carbonyl groups [formula (IV)] being tertiary which means that they are either substituted (as mentioned above) or included in an unsaturated or aromatic ring having 5 or 6 atoms, preferably a benzene ring.

As specific examples of ketones that can be used in the process of the invention, there may be mentioned more particularly:

- benzophenone - 2-methylbenzophenone

2,4-dimethylbenzophenone

4,4'-dimethylbenzophenone

2,2'-dimethylbenzophenone 4,4'-dimethoxybenzophenone

4-benzoylbiphenyl

- fluorenone

Examples of alcohols and carbonyl compounds used in the process of the invention are given below: 1-decanol, 1-decanol, isopropyl mandelate, anisaldehyde, terephthaldehyde , phenanthrene-9,10-dione.

Base Optionally intervenes in the process of the invention, a base whose function is to trap the leaving group which is a hydracid.

The characteristic of the base is that it has a pka at least greater than or equal to 4, preferably between 5 and 14, and more preferably between 7 and 11. ^" The pKa is defined as the ionic dissociation constant of the acid pair. / base, when water is used as a solvent.

For the choice of a base having a pKa as defined by the invention, reference may be made, inter alia, to the Handbook of Chemistry and Physics, 66 edition, p. D-161 AND D-162. Another imperative that governs the choice of the base is that it is non-nucleophilic that is to say that it does not replace the substrate in the reaction.

Another characteristic of the base is that it is preferable that it be soluble in an organic medium.

Among the bases which are suitable for the process of the invention, mention may be made, inter alia, of mineral bases such as carbonates, hydrogencarbonates, phosphates, hydrogen phosphates of alkali metals, preferably of sodium, of potassium, of cesium or of alkaline earth metals preferably calcium, barium or magnesium.

Organic bases such as tertiary amines and more particularly triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine and N, N-diethylcyclohexylamine are also suitable. pyridine, 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, N- [7-butylpiperidine, 1,2-dimethylpiperidine, N-methylpyrrolidine, 1,2-dimethylpyrrolidine.

Among the bases, triethylamine is preferably chosen. The amount of base used expressed relative to the pyridinium salt is at least equal to the stoichiometric amount. More preferentially, it is such that the ratio between the number of moles of pyridinium salt and the number of moles of base preferably varies between 1 and 3 and even more preferably between 1, 5 and 2.

Source of fluoride

The fluoride is introduced into the medium in the form of salt (s). By way of example, mention may be made of hydrofluoric acid; salts such as, for example, potassium fluoride or ammonium fluoride.

It is also possible to use quaternary ammonium fluorides, preferably tetraalkylammonium fluorides, and more particularly tetrapropylammonium, tetrabutylammonium; tetraalkylammonium hydrogenodifluoride, preferably ammonium hydrogen difluoride.

In a preferred manner, tetrabutylammonium fluoride (TBAT) is selected.

The amount of fluoride source used expressed relative to the oxygenated substrate is at least equal to the stoichiometric amount. More preferably, it is such that the ratio of the number of moles of fluoride. and the number of moles of substrate (alcohol or ketone) preferably varies between 1 and 3 and even more preferably between 1, 5 and 2.

Organic solvent

The reaction is generally conducted in the presence of a reaction solvent. A solvent is chosen which is inert under the reaction conditions.

As more specific examples of solvents that are suitable for the present invention, mention may be made preferably of aprotic polar solvents such as dimethylsulfoxide, sulfolane or linear or cyclic carboxamides, such as Λ /, Λ-dimethylacetamide (DMAC), Λ /, Λ-diethylacetamide, dimethylformamide (DMF), diethylformamide; the alpha or aromatic nitriles, preferably acetonitrile, propionitrile, butanenitrile, isobutanenitrile, pentanenitrile, 2-methylglutaronitrile, adiponitrile, benzonitrile, tolunitrile, malonitrile, 1,4-benzonitrile.

As other examples of less polar organic solvents suitable for the invention, mention may in particular be made of halogenated or non-halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons; ether-oxides. It is also possible to use aliphatic and cycloaliphatic hydrocarbons, more particularly paraffins, such as, in particular, hexane, heptane, octane, isooctane, nonane, decane, undecane, tetradecane and ether. oil and cyclohexane; with aromatic hydrocarbons such as, in particular, benzene, toluene, xylenes, ethylbenzene, diethylbenzenes, trimethylbenzenes, cumene, pseudocumene, petroleum fractions consisting of a mixture of alkylbenzenes, especially the Solvesso® type cuts.

It is also possible to use aliphatic or aromatic halogenated hydrocarbons, more particularly mention may be made of perchlorinated hydrocarbons such as in particular tetrachlorethylene, hexachloroethane; partially chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, trichlorethylene, 1-chlorobutane, 1,2-dichlorobutane; monochlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene or mixtures of different chlorobenzenes.

Dichloromethane or chloroform is preferably chosen.

Examples of solvents that may be mentioned are aliphatic, cycloaliphatic or aromatic ether-oxides and, more particularly, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tertiobutyl ether, dipentyl ether, diisopentyl ether, ethylene glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol dimethyl ether (or 1,5-dimethoxy-3-oxapentane), dioxane, tetrahydrofuran.

It is also possible to use a mixture of organic solvents.

The amount of organic solvent used is chosen in a preferential manner such that the weight concentration of the starting substrate in the solvent is between 5 and 40%, preferably between 10 and 20%.

The reaction is generally carried out at a temperature of between 0 ^° C. and 140 ^° C., preferably between 80 ^° C. and 100 ° C.

The fluorination reaction is generally carried out under atmospheric pressure, but preferably under a controlled atmosphere of inert gases. It is possible to establish an atmosphere of rare gases, preferably argon, but it is more economical to use nitrogen. A pressure slightly above or below atmospheric pressure may be suitable.

From a practical point of view, the reaction is simple to implement. The order of implementation of the reagents is not critical. A preferred alternative is to charge the substrate, the solvent and the fluorinating agent and then the base and heat to the desired temperature.

The duration of the reaction is very variable. It can go from 1 to 24 hours and is preferably between 8 and 15 hours.

At the end of the reaction, the fluorinated product is recovered by implementing the usual techniques of a person skilled in the art.

Generally, water is added to solubilize the salts in aqueous phase and an immiscible solvent, for example, dichloroethane, toluene or monochlorobenzene to recover the fluorinated compound obtained in the organic phase.

The aqueous and organic phases are then separated.

The fluorinated compound is recovered by conventional separation methods, for example by distillation or by crystallization in a suitable solvent, in particular an ether such as isopropyl ether or an alcohol such as methanol, ethanol or isopropanol.

The fluorination reagents according to the invention comprising the units (F) or (Fi) can be prepared in a conventional manner. Reference can be made in particular to the work of P. H. Gross et al, [J. Org.

Chem. (1991), 56, 509-513) for the preparation of 2-fluoro-N-methylpyridinium tosylate and Marvell et al., J. Am. Chem. Soc. (1929), 51, 3640 for the preparation of 2-chloro-N-methylpyridinium tosylate.

One way of accessing said reagents is to perform an alkylation reaction of a 2-halopyridine which may be represented by the following formula:

in said formula, X1 represents a fluorine, chlorine, bromine or iodine atom. As alkylating agents, it is possible to use alkyl halides, preferably having a low carbon C ₁ -C ₄ condensation and preferably methyl iodide or bromide.

It is also possible to use a sulphonic acid or carboxylic acid halide which may be represented by the following formulas: R ₃ SO ₃ X ₂ (VI) and R _b CO ₂ X ₂ (VII) in which R _a and R _b have the meaning given above and X ₂ represents a halogen atom, chlorine, bromine or iodine. The 2-halopyridine is reacted with an alkylating agent as mentioned above.

Generally the alkylating agent is in slight excess, the molar ratio between the alkylating agent and 2-halopyridine advantageously varies between 1, 1 and 1, 2.

The temperature of the alkylation reaction is generally between 0 ^° C. and 80 ^° C., preferably between 20 ^° C. and 50 ^° C.

The reaction is conducted in the presence of an inert organic solvent under the reaction conditions. Examples of solvents that may be mentioned include aliphatic or aromatic hydrocarbons, halogenated or otherwise, or nitriles. We can refer to the lists previously established in this text

Dichloromethane, chlorobenzene and toluene are preferred.

The pyridinium salt formed precipitates in the reaction medium. The precipitate is recovered by conventional solid / liquid separation techniques, preferably by filtration.

The precipitate may be washed, preferably with the aid of the organic solvent used in the reaction, and the solvent is removed by evaporation.

It is then implemented in the process of the invention. According to a variant of the invention, it is possible to prepare the 1-alkyl- or

1-cycloalkyl-2-fluoropyridinium from a reagent comprising another halogen, for example a 1-alkyl- or 1-cycloalkyl-2-chloropyridinium by performing the exchange of chlorine with a fluorine atom, using an alkali metal fluoride, preferably sodium or potassium. The starting reagent is suspended in an organic solvent such as, for example, acetonitrile, and then the alkali metal fluoride is added in powder form in an amount ranging from stoichiometric to excess amount, for example %.

The alkali metal chloride formed is separated by conventional solid / liquid separation techniques, preferably by filtration.

The fluorinated reagent is then recovered.

Examples of embodiments of the invention given below are given by way of non-limiting illustration. The yield defined in the examples corresponds to the ratio between the number of moles of product formed and the number of moles of substrate involved. Examples A to K relate to the preparation of the fluorination reagent and the following examples, their use for preparing monofluorinated compounds (Examples 1 to 5) or di- or polyfluorinated compounds (Examples 6 to 8).

Examples

Example A

Preparation of 2-chloro-N-methylpyridinium tosylate

In a 25-ml flask surmounted by a refrigerant, 2-chloropyridine

(2.3 g, 20.6 mmol) and the methyl tosylate (3.83 g, 20.6 mmol) are heated at 80-85 ^° C. for one hour.

Hot toluene (15 ml) is then added before the mixture cools and crystallizes. The whole is left stirring for 10 minutes and the mixture is allowed to rise to room temperature.

The crystallized bottom phase is recovered.

The product is in the form of a white solid and is obtained with a yield of 88% (5.4 g). The NMR characteristics are as follows:

¹ H NMR (300 MHz, CDCl ₃ ): 2.26 (s, 3H); 4.35 (s, 3H); 7.04 (d, J = 8 Hz, 2H); 7.56 (d, J = 8 Hz, 2H); 7.85-7.91 (m, 2H); 8.38-8.44 (m, 1H); 9, 34 (d, J = 5.3 Hz, 1H)

¹³ C NMR (75 MHz, CDCl ₃ ): Primary: 21.3; 47.8

Secondary: -

Tertiaries: 125.7; 126, 7 (2C); 128.8 (2C); 129.5; 149.6; 154.5

Quaternaries: 140.1; 143.4; 147.4

Example B:

Preparation of 2-chloro-N-methylpyridinium triflate

Tf

In a 25 ml flask, 2-chloropyridine (2 g, 20.6 mmol) is diluted in 15 ml of toluene.

To this solution is added to the syringe methyl triflate (2.33 ml, 20.6 mmol). The mixture is stirred magnetically at room temperature for one hour.

The precipitate is then filtered on Bϋchner.

The traces of solvent are removed by evaporation under reduced pressure of about 20 mm of mercury. The product is in the form of a white solid and is obtained with a yield of 99%.

The NMR characteristics are as follows:

- ¹ H NMR (300 MHz, DMSO): 4.33 (s, 3H); 8.08 (ddd, J = 7.6 Hz, J = 6.2 Hz, J = 1.3 Hz, 1H); 8.37 (dd, J = 8.3Hz, J = 1.3Hz, 1H), 8.58 (ddd, J = 8Hz, J = 8Hz, J = 1.6Hz, 1H); 9.16 (dd, J = 6.2 Hz, J = 1.6Hz, 1H)

¹³ C NMR (75 MHz, DMSO): Primary: 47.3 Secondary: -

Tertiaries: 126.1; 129.4; 147.0; Quaternary 148.2: 170.6 (q, J = 322.2Hz); 121, 1 (q, J = 322Hz)

Example C

Preparation of 2-fluoro-N-methylpyridinium tosylate from 2-fluoropyridine: In a 25 ml flask surmounted by a condenser, 2-fluoropyridine (2 g,

20.6 mmol) is diluted in 15 ml of toluene.

To this solution is added to the syringe the methyl tosylate (3.83 g, 20.6 mmol).

The mixture is refluxed with magnetic stirring overnight. During the reaction appears a second yellow phase which crystallizes at room temperature.

The precipitate is then filtered on Bϋchner.

The traces of solvent are removed by evaporation under reduced pressure of about 20 mm of mercury. The product is in the form of a yellow solid and is obtained with a yield of 89% (5.16 g).

Example D: Preparation of 2-fluoro-N-methylpyridinium tosylate from 2-chloro N-methylpyridinium tosylate

In a 50 ml flask surmounted by a condenser, the 2-chloro N-methylpyridinium tosylate (4.77 g, 15.9 mmol) is dissolved in 20 ml of acetonitrile. To this solution is added potassium fluoride "spray dried" (1.02 g,

17.5 mmol, 1.1 eq) previously dried under reduced pressure of about 20 mm Hg.

Everything is refluxed for one hour.

The potassium chloride is filtered on Bϋchner after cooling the solution.

The filtrate is concentrated under reduced pressure of approximately 20 mm of mercury and then redissolved in 100 ml of dichloromethane.

The mixture is filtered again which eliminates excess potassium fluoride. The filtrate is again concentrated under reduced pressure of about 20 mm Hg.

The recovered solid is then triturated in methyl-t-butyl ether for one hour and then the mixture is filtered.

The product is in the form of a yellow solid and is obtained with a yield of 90%.

The NMR characteristics are as follows:

¹ H NMR (300 MHz, CDCl ₃ ): 2.31 (s, 3H); 4.29 (d, J = 3.8 Hz, 3H); 7, 10 (d, J = 8 Hz, 2H); 7.58 (d, J = 8 Hz, 2H); 7.62 (dd, J = 8.4 Hz, J = 4.2 Hz, 1H); 7.79 (m, 1H); 8.52 (m, 1H); 9.07 (m, 1H) - ¹³ C NMR (75 MHz, CDCl ₃ ):

Primary: 21, 3; 42.0 (d, J = 5.3 Hz) Secondary: -

Tertiary: 114.0 (d, J = 19.9 Hz); 124.3 (d, J = 3.8 Hz); 125, 8 (2C); 128.8 (2C); 145.8 (d, J = 7.7 Hz); 150.9 (d, J = HHz) Quaternaries: 139.9; 142.6; 158.6 (d, J = 278.3Hz)

Example E:

Preparation of 2-fluoro-N-methylpyridinium triflate from 2-fluoropyridine:

Tf

In a 25 ml flask, 2-fluoropyridine (2 g, 20.6 mmol) is diluted in 15 ml of toluene.

To this solution is added to the syringe methyl triflate (2.33 ml, 20.6 mmol). After a few minutes a white precipitate has formed.

The mixture is stirred magnetically at room temperature for one hour.

The precipitate is then filtered on Bϋchner.

The traces of solvent are removed by evaporation under reduced pressure of about 20 mm of mercury.

The product is in the form of a white solid and is obtained with a yield of 99%.

Example F: Preparation of 2-fluoro-N-methylpyridinium triflate from triflate of

2-chloro N-methylpyridinium:

In a 50 ml flask surmounted by a condenser, 2-chloro-N-methylpyridinium triflate (2.7 g, 10 mmol) is dissolved in 15 ml of acetonitrile.

To this solution is added potassium fluoride "spray dried" (0.64 g, 11 mmol, 1.1 eq) previously dried under reduced pressure of about 20 mm of mercury when hot.

Everything is refluxed for one hour.

The potassium chloride is filtered on Bϋchner after cooling the solution. The filtrate is concentrated under reduced pressure of approximately 20 mm of mercury and then redissolved in 100 ml of dichloromethane.

The solid is again filtered and dried under reduced pressure of 20 mm Hg.

The NMR characteristics are as follows:

¹ H NMR (300 MHz, DMSO): 4.11 (d, J = 4.1 Hz, 3H), 7.86 (m, 1H), 7.98 (dd, J = 4.5 Hz, J = 8 Hz ), 8.62 (m, 1H), 8.80 (m, 1H)

¹³ C NMR (75 MHz, DMSO): Primary: 41.9 (d, J = 5.3 Hz)

Secondary: -

Tertiary: 114.6 (d, J = 20.3Hz); 124.2 (d, J = 3.7 Hz); 144.9 (d, J = 7.6 Hz); 151, 2

(d, J = 11, 6Hz) Quaternary: 157.8 (d, J = 276.7Hz)

Example G:

Preparation of 2-fluoro N-methylpyridinium fluoride from 2-fluoro N-methylpyridinium triflate

In a 100 ml flask, 2-fluoro-N-methylpyridinium triflate (10 mmol) is dissolved in a minimum of acetonitrile (5 ml).

To this mixture is added the TBAT dissolved in 50 ml of dichloromethane.

A white precipitate forms immediately. The latter is filtered on Bϋchner and washed with dichloromethane.

The solid is then dried under reduced pressure of about 20 mm Hg.

Example H: Preparation of 2-fluoro-N-methylpyridinium fluoride from the triflate of

2-fluoro N-methylpyridinium:

In a 25 ml flask, the 2-fluoro-N-methylpyridinium tosylate (10 mmol) is dissolved in 10 ml of dichloromethane.

To this mixture is added the TBAT dissolved in 10 ml of dichloromethane. A white precipitate forms immediately.

The latter is filtered on Bϋchner and washed with dichloromethane. The solid will then be dried under reduced pressure of about 20 mm Hg.

Ion exchange is quantitative regardless of the method. The NMR characteristics are as follows:

¹ H NMR (300 MHz, DMSO): 4.11 (d, J = 4.1Hz, 3H), 7.86 (ddd, J = 1.2Hz, J = 6.3Hz, J = 7.5Hz , 1H), 7.99 (ddd, J = 1Hz, J = 4.6Hz, J = 8.6Hz), 8.62 (m, 1H), 8.81 (ddd, J = 1, 8Hz, J = 4.6Hz, J = 6.3Hz, 1H)

¹³ C NMR (75 MHz, DMSO): Primary: 41.6 (d, J = 5 Hz)

Secondary: -

Tertiary: 114.3 (d, J = 20.3 Hz); 123.9 (d, J = 3.8 Hz); 144.8 Hz (d, J = 7.6 Hz); 150.8 (d, J = 11, 6Hz) Quaternary: 158.9 (d, J = 271, 9Hz)

Example I:

Preparation of N-methyl-2-chloroquinolinium triflate

In a 50 ml flask, 2-chloroquinoline (20 mmol) is dissolved in 30 ml of toluene.

The mixture is cooled in an ice bath and methyl triflate (1.1 eq) is added.

The whole is left stirring for 8 hours at room temperature. The precipitated white solid is then filtered and washed with toluene. It is then dried under reduced pressure of approximately 20 mm of mercury. The quinolinium salt is obtained with a yield of 95%. The NMR characteristics are as follows:

¹ H NMR (CDCl ₃ , 300 MHz):, 80 (s, 3H); 7.97 (m, 1H); 8.04 (d, J = 8.8 Hz, 1H); 8.22-8.3 (m, 2H); 8.47 (d, J = 9.5 Hz, 1H); 8.94 (d, J = 8.8 Hz, 1H)

Example J Preparation of N-methyl-2-fluoroquinolinium triflate

The same procedure is used as for obtaining N-methyl-2-fluoropyridinium triflate from N-methyl-2-chloropyridinium triflate with similar yields.

Example K:

Preparation of N-methyl-2-fluoroquinolinium fluoride

The same procedure is used as for obtaining N-methyl-2-fluoropyridinium fluoride from N-methyl-2-fluoro-pyridinium triflate with similar yields. Example 1

Preparation of 1-fluorodecane

In a flask of 5 ml, hydrogendifluoride tetrabutylammonium (560 mg, 2 mmol) was dried under reduced pressure of1 mm Hg at 100 ° C for A hour ^Λ.

After cooling, triethylamine (0.14 ml, 1 mmol) is added. The whole is dissolved in chloroform, then 1-decanol (158 mg, 1 mmol) and 1-methyl-2-fluoropyridinium tosylate (560 mg, 2 mmol) are added. The mixture is refluxed with chloroform for 5 hours.

It is then hydrolysed with 2 ml of water and neutralized with a saturated aqueous solution of sodium monohydrogen carbonate. The extraction is carried out with 4 times 5 ml of petroleum ether. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of 250 mm Hg.

The residue is purified by chromatography on a silica column (eluent: petroleum ether).

After evaporation, the product is then in the form of a transparent liquid and is obtained with a yield of 56% (m = 90 mg). The NMR characteristics are as follows:

¹ H NMR (CDCl ₃ , 300 MHz): 0.81 (t, J = 8 Hz, 3H); 1, 1-1, 3 (m, 14H); 1.5-1.7 (m, 2H); 4.37 (dt, J = 47.4 Hz, J = 6.2 Hz, 2H)

¹³ C NMR (CDCl ₃ , 75 MHz): Primary: 14.1 Secondary: 22.7; 25.2; 25.3; 29.3 (d, J = 4Hz); 29.5; 30.4 (d, J = 19 Hz); 31.9; 84.3 (d, J = 164 Hz) Tertiary: - Quaternary: -

Example 2

Preparation of 2-fluorodecane

F

In a flask of 5 ml, hydrogendifluoride tetrabutylammonium (560 mg, 2 mmol) was dried under reduced pressure of 1 mm of mercury at 100 ⁰ C for ^Λ A hour.

After cooling, triethylamine (0.14 ml, 1 mmol) is added. The whole is dissolved in chloroform and then 2-decanol (158 mg, 1 mmol) and the tosylate of 1-methyl-2-fluoropyridinium (560 mg, 2 mmol) are added.

The mixture is refluxed with chloroform for 5 hours. It is then hydrolysed with 2 ml of water and neutralized with a saturated aqueous solution of sodium monohydrogen carbonate.

The extraction is carried out with 4 times 5 ml of petroleum ether.

The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of 250 mm Hg. The residue is purified by chromatography on a silica column (eluent: petroleum ether).

The product is then in the form of a transparent liquid and is obtained with a yield of 43% (m = 69 mg).

The NMR characteristics are as follows: ¹ H NMR (CDCl ₃ , 300 MHz): 0.75-0.85 (m, 6H); 1-1.3 (m, 14H); 4.37 (m, 1H) - ¹³ C NMR (CDCl ₃ , 75 MHz): Primary: 14.1; 21.0 (d, J = 23 Hz)

Secondary: 22.3; 22.6; 25.1 (d, J = 5 Hz); 29.2; 29.5 (d, J = 2 Hz); 31, 9; 37.0 (d, J = 21 Hz) Tertiary: 91.1 (d, J = 164 Hz) Quaternary: -

Example 3

Preparation of 2-fluoro-1,2-diphenylethanone

In a 5 ml flask, the tetrabutylammonium hydrogen difluoride (280 mg, 1 mmol) is dried under reduced pressure of 1 mm of mercury at 100 ^° C. for one hour. After cooling, triethylamine (0.07 ml, 1 mmol) is added.

The whole is dissolved in chloroform and then benzoin (106 mg, 0.5 mmol) and the tosylate of 1-methyl-2-fluoropyridinium (280 mg, 1 mmol) are added.

The mixture is refluxed with chloroform overnight. It is then hydrolysed with 2 ml of water and neutralized with a saturated aqueous solution of sodium monohydrogen carbonate. The extraction is carried out with 4 times 5 ml of ethyl ether.

The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure of 20 mm Hg.

The residue is purified by chromatography on a silica column (eluent: petroleum ether / dichloromethane 1/1, Rf = 0.25).

The product is then in the form of a white solid (melting point 53 ° C.) and is obtained with a yield of 87% (m = 93 mg).

The NMR characteristics are as follows:

- ¹ H NMR (CDCl _3, 300 MHz): 6.52 (d, J = 48.7 Hz ₁ H); 7.3-7.6 (m, 8H); 7.9-8.0 (m, 2H)

- ¹³ C NMR (CDCl ₃ , 75 MHz): Primary: - Secondary: -

Tertiary: 94.0 (d, J = 186 Hz); 127.3 (d, J = 6 Hz); 128.7; 129.1; 129.1; 129.6 (d, J = 3 Hz); 133.8

Quaternaries: 134.1; 134.3 (d, J = 20Hz); 194.3 (d, J = 21 Hz)

Example 4

Preparation of ethyl fluoro-phenylacetate:

In a 5 ml flask, tetrabutylammonium hydrogen difluoride

(280 mg, 1 mmol) is dried under reduced pressure of 1 mm of mercury, 100 ^° C. for 14 hours.

After cooling, triethylamine (0.07 ml, 1 mmol) is added. The whole is dissolved in chloroform (1 ml) and then the ethyl mandelate (90 mg, 0.5 mmol) and the tosylate of 1-methyl-2-fluoropyridinium (280 mg, 1 mmol) are added.

The mixture is refluxed with chloroform for three hours. It is then hydrolyzed with 5 ml of water. The extraction is carried out with 3 times 5 ml of ethyl ether. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of approximately 20 mm of mercury.

The residue is purified by chromatography on a silica column (eluent: petroleum ether / dichloromethane 1/1).

The product is then in the form of a colorless liquid and is obtained with a yield of 56% (m = 51 mg). The NMR characteristics are as follows: ¹ H NMR (CDCl ₃ , 300 MHz):

1, 29 (t, J = 7.3 Hz, 3H); 4.25 (q, J = 7.3 Hz, 2H); 5.76 (d, J = 48.2 Hz, 1H); 7.10-7.48 (m, 5H)

Example 5

Preparation of isopropyl fluoro-phenylacetate:

In a 5 ml flask, the tetrabutylammonium hydrogen difluoride (280 mg, 1 mmol) is dried under reduced pressure of 1 mm of mercury at 100 ^° C. for 12 hours.

After cooling, triethylamine (0.07 ml, 1 mmol) is added. The whole is dissolved in chloroform (1 ml) and then isopropyl mandelate (90 mg, 0.5 mmol) and 1-methyl-2-fluoropyridinium tosylate (280 mg, 1 mmol) are added. The mixture is refluxed with chloroform for three hours.

It is then hydrolyzed with 5 ml of water. The extraction is carried out with 3 times 5 ml of ethyl ether. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of approximately 20 mm of mercury. The residue is purified by chromatography on a silica column (eluent: petroleum ether / dichloromethane 1/1).

The product is then in the form of a colorless liquid and is obtained with a yield of 63% (m = 62 mg). The NMR characteristics are the following: ¹ H NMR (CDCl ₃ , 300 MHz): 1.20 (t, d = 6.3 Hz, 3H), 1, 30 (t, d = 6.3 Hz, 3H) ; 5.12 (spt, J = 6.3 Hz, 1H); 5.76 (d, J = 48.0 Hz, 1H); 7.10-7.48 (m, 5H) - ¹³ C NMR (CDCl ₃ , 75 MHz) Primary: 21.5; 21.7 Secondary: - Tertiary: 69.7; 89.4 (d, J = 185 Hz); 126.6; 127.9; 128.7 Quaternaries: 134.6 (d, J = 38 Hz); 168.1 (d, J = 27 Hz) Example 6

Preparation of 1-difluoromethyl-4-methoxybenzene

In a flask of 25 ml is introduced tetrabutylammonium hydrogenodifluoride monohydrate (3 g, 10 mmol, 3.3 eq).

The latter is heated at 100 ^° C. in an oil bath under reduced pressure of 1 mm of mercury for one hour.

After cooling under argon, 1-methyl-2-fluoropyridinium tosylate (2.8 g, 10 mmol, 3.3 eq) is introduced followed by anisaldehyde (408 mg, 3 mmol) and triethylamine (1, 4 ml, 10 mmol, 3.3 eq).

After stirring for 5 minutes, the mixture is then heated to 80 ^° C. and becomes completely homogeneous.

After 5 hours the mixture is hydrolyzed with water (5 ml), neutralized with saturated sodium hydrogencarbonate solution (10 ml). The aqueous solution is then extracted with diethyl ether (3 times 20 ml).

The organic phase is dried over magnesium sulfate. After filtration, the solvent is evaporated under reduced pressure of approximately 20 mm of mercury.

The black liquid residue exhibited, in thin-layer chromatography, two spots with Rf respectively 0.27 and 0.71 (petroleum ether / dichloromethane 1: 1) or 0.08 and 0.41 (petroleum ether / dichloromethane 3: 1 ).

Silica column chromatography is carried out eluting with a 3: 1 to 1: 1 petroleum / dichloromethane gradient.

1-Difluoromethyl-4-methoxybenzene is in the form of a slightly yellow oil (278 mg, 1.76 mmol, 59%).

The recovered anisaldehyde is a white solid (100 mg, 0.73 mmol, 24%). The NMR characteristics are as follows:

¹ H NMR (CDCl ₃ , 300 MHz): 3.85 (s, 3H); 6.62 (t, J = 56.8 Hz, 1H); 6.96 (d, J = 8.9 Hz, 2H); 7.45 (d, J = 8.9 Hz, 2H) - ¹³ C NMR (CDCl ₃ , 75 MHz): Primary: 55.34 Secondary: Tertiary: 114.0; 114.9 (t, J = 237 Hz); 127.1 (t, J = 6Hz) Quaternaries: 126.5 (t, J = 23 Hz), 161, 4

Example 7

Preparation of 1,4-bistrifluoromethylbenzene

In a 5 ml flask, tetrabutylammonium hydrogen difluoride

(750 mg, 2.5 mmol) is dried under reduced pressure of 1 mm of mercury at 100 ^° C. for 1 hour.

After cooling, triethylamine (0.35 ml, 2.5 mmol), 1-methyl-2-fluoropyridinium tosylate (700 mg, 2.5 mmol) and then terephthaldehyde (36 mg, 0.25 mmol) are added .

The whole is heated at 80 ^° C. for 6 hours.

It is then hydrolyzed with 3 ml of water and _neutralized with a saturated aqueous solution of sodium monohydrogencarbonate (3 ml).

The extraction is carried out with 3 times 5 ml of ethyl ether. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of approximately 20 mm of mercury.

The residue is purified by chromatography on a silica column (eluent: gradient of dichloromethane in petroleum ether).

The product is then in the form of a colorless liquid and is obtained with a yield of 30% (m = 13 mg).

4-Difluoromethylbenzaldehyde is isolated with a yield of 20% (8 mg).

The chromatography results are: Eluent: Petroleum ether / Dichloromethane 1/1 Developer: UV

Front End Reference: Rf ₁ = 0.8 Rf ₂ = 0.27 The NMR characteristics are as follows:

¹ H NMR (CDCl ₃ , 300 MHz): 6.70 (t, J = 56.5 Hz, 2H); 7.62 (s, 4H)

- ¹³ C NMR (CDCl ₃ , 75 MHz): Primary: - Secondary: - Tertiary: 114.0 (t, J = 239 Hz); 126.0 (t, J = 6 Hz) Quaternary: 136.7 (t, J = 22 Hz)

4-difluoromethylbenzaldehyde: ¹ H NMR (CDCl ₃ , 300 MHz): 6.71 (t, J = 55.9 Hz, 1H); 7.70 (d, J = 7.9 Hz, 2H); 7.99 (d, J = 7.9 Hz, 2H); 10.09 (s, 1H)

Example 8

Preparation of 10,10-difluorophenantren-9-one:

In a 10 ml flask, the tetrabutylammonium hydrogen difluoride (2.8 g, 10 mmol) is dried under reduced pressure of 1 mm Hg at 100 ^° C. for 1 hour.

After cooling, triethylamine (0.7 ml, 10 mmol) and 1-methyl-2-fluoropyridinium tosylate (2.8 g, 10 mmol) are added.

The whole is left with magnetic stirring until a homogeneous solution is obtained (a slight heating may be necessary).

Phenantrene-9,10-dione (208 mg, 1 mmol) is then added and the mixture is heated at 80 ^° C. overnight. It is then hydrolyzed with 3 ml of water and neutralized with a saturated aqueous solution of sodium monohydrogen carbonate. The extraction is carried out with 4 times 10 ml of ethyl ether. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of approximately 20 mm of mercury. The residue is purified by chromatography on a silica column (eluent: petroleum ether / dichloromethane 1/1, Rf = 0.3).

The product is then in the form of a white solid (melting point 90 ^° C.) and is obtained with a yield of 58% (m = 124 mg).

The NMR characteristics are as follows: ¹ H NMR (CDCl ₃ , 300 MHz): 7.48 (m, 2H); 7.61 (tq, J = 1.3 Hz, J = 7.5 Hz, 1H); 7.74 (ddd, J = 1.5 Hz, J = 7.5 Hz, J = 8 Hz, 1H); 7.87 (dd, J = 1 Hz, J = 7.7 Hz, 1H); 7.94 (m, 2H); 8.09 (ddd, J = 0.5 Hz, J = 1.5 Hz, J = 7.7 Hz, 1H) - ¹³ C NMR (CDCl ₃ , 75 MHz): Primary: - Secondary: -

Tertiaries: 123.7; 124.4; 127.3 (t, J = 5 Hz); 128.8 (t, J = 1 Hz); 129.3; 129.6 (t, J = 1 Hz); 132.4 (t, J = 2 Hz); Quaternary 136.2: 108.0 (t, J = 245 Hz); 127.7 (t, J = 2 Hz); 130.2 (t, J = 23 Hz); 131.7 (t, J = 6 Hz); 136.1 (t, J = 2 Hz); 186.9 (t, J = 26 Hz)

Claims

1 - Process for preparing a mono- or difluorinated hydrocarbon compound from an alcohol or a carbonyl compound which comprises the reaction of one of them with a fluorination reagent, optionally in the presence of a base characterized in that the fluorinating agent is a reagent comprising a pyridinium unit having the following formula:

in said formula: - Ro represents an alkyl or cycloalkyl group.

2 - Process according to claim 2 characterized in that the fluorination reagent is prepared in situ by using, associated with a fluoride source, a halogenated reagent comprising a pyridinium unit corresponding to the following formula:

in said formula:

X represents a halogen atom of higher rank than fluorine, preferably chlorine, bromine or iodine, preferably chlorine, - R ₀ represents an alkyl or cycloalkyl group.

3 - Method according to one of claims 1 and 2 characterized in that the fluorination reagent comprises a unit having the formula (F) or (Fi) included in a polycyclic structure, preferably, the pyridinium cycle is attached to a ring having 5 or 6 carbon atoms, saturated, unsaturated or aromatic.

4 - Method according to one of claims 1 to 3 characterized in that the fluorinating reagent comprises a unit having the formula (F) or (F) in which Ro represents an alkyl group Ci-C _4, preferably a methyl group. 5 - Process according to one of claims 1 to 4 characterized in that the fluorination reagent comprises a pyridinium unit in which the quaternized nitrogen atom is associated with a counterion Y ^" selected from halides, the groups sulfonate or carboxylate.

6 - Process according to one of claims 1 to 5 characterized in that the fluorination reagent is chosen from:

2-fluoro-N-methylpyridinium tosylate,

2-fluoro-N-methylpyridinium triflate, 2-fluoro-N-methylpyridinium fluoride,

triflate of N-methyl-2-fluoroquinolinium,

N-methyl-2-fluoroquinolinium fluoride.

7 - Process according to one of claims 1 to 6 characterized in that the alcohol corresponds to the general formula (I):

R ₁ - OH (I) in said formula (I):

R 1 represents a hydrocarbon group having from 1 to 30 carbon atoms, which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic cycloaliphatic group; a saturated or unsaturated, linear or branched, aliphatic group carrying a cyclic substituent.

8 - Process according to one of claims 1 to 6 characterized in that the carbonyl compound is an aldehyde or a ketone (or dione) corresponding to one of the general formulas:

⁰ (II) or ^Rs (III) or ^R5 (IV) in said formulas:

the groups R ₄ and R ₅ may be bonded together to form a ring comprising 5 or 6 atoms, - The groups R ₄ and Rs do not include hydrogen atoms on the carbon atom in position α relative to the carbonyl group.

9 - Process according to one of claims 1 to 8 characterized in that the ratio between the number of moles of fluorination reagent and the number of moles of substrate varies between 1 and 3 and is preferably between 1, 5 and 2.

10 - Method according to one of claims 1 to 9 characterized in that it implements a base whose pka is at least greater than or equal to 4, preferably between 5 and 14, and more preferably between 7 and 11.

11 - Process according to claim 10 characterized in that the base is a mineral base, preferably a carbonate, hydrogencarbonate, phosphate, hydrogen phosphate of alkali metal, preferably sodium, potassium, cesium or alkaline earth metal, preferably calcium, barium or magnesium or an organic base, preferably a tertiary amine.

12 - Process according to claim 2 characterized in that the source of fluoride is hydrofluoric acid; a salt, preferably potassium fluoride or ammonium fluoride; a quaternary ammonium fluoride, preferably tetrabutylammonium fluoride.

13 - Method according to one of claims 1 to 12 characterized in that it uses an organic solvent selected from dimethylsulfoxide, sulfolane or linear or cyclic carboxamides, preferably N, N-dimethylacetamide (DMAC) , N, N-diethylacetamide, dimethylformamide (DMF), diethylformamide; the alpha or aromatic nitriles, preferably acetonitrile; aliphatic, cycloaliphatic or aromatic halogenated or non-halogenated hydrocarbons; ether-oxides.

14 - Method according to one of claims 1 to 13 characterized in that the fluorination reaction is carried out at a temperature between O ⁰ C and 14O ⁰ C, preferably between 80 ⁰ C and 100 ⁰ C.

15 - Process according to one of claims 1 to 14, characterized in that a monofluorinated compound is obtained from an alcohol which preferably corresponds to formula (I). 16 - Process according to one of claims 1 to 14, characterized in that a gem-difluorinated compound is obtained from a carbonyl compound which preferably corresponds to one of the formulas (II) to (IV).